The present invention relates to a novel amine salt of an integrin receptor antagonist. More particularly, the invention relates to the tris(hydroxymethyl)aminomethyl (xe2x80x9cTRISxe2x80x9d) salt of 3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid, which is a potent integrin xcex1vxcex23 receptor antagonist. The xe2x80x9cTRISxe2x80x9d salt of the present invention is therefore useful for the treatment and prevention of diseases and conditions for which an antagonist of the integrin xcex1vxcex23 receptor is indicated.
Integrin xcex1vxcex23 receptor antagonists have been described as being of use for the prevention and/or treatment of osteoporosis, vascular restenosis, macular degeneration, diabetic retinopathy, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth [see, for example, M. E. Duggan, et al., xe2x80x9cLigands to the integrin receptor xcex1vxcex23, Exp. Opin. Ther. Patents, 10: 1367-1383 (2000); M. Gowen, et al., xe2x80x9cEmerging therapies for osteoporosis,xe2x80x9d Emerging Drugs, 5: 1-43 (2000); J. S. Kerr, et al., xe2x80x9cSmall molecule xcex1v integrin antagonists: novel anticancer agents,xe2x80x9d Exp. Opin. Invest. Drugs, 9: 1271-1291 (2000); and W. H. Miller, et al., xe2x80x9cIdentification and in vivo efficacy of small-molecule antagonists of integrin xcex1vxcex23 (the vitronectin receptor),xe2x80x9d Drug Discovery Today, 5: 397-408 (2000)].
U.S. Pat. No. 6,048,861, assigned to Merck and Co., describes a class of 9-substituted-3-aryl-nonanoic acid derivatives, which are potent integrin xcex1vxcex23 receptor antagonists and therefore useful for inhibiting bone resorption, vascular restenosis, treating and/or preventing osteoporosis, and inhibiting diseases and conditions associated with excessive and undesirable angiogenesis. Specifically disclosed in U.S. Pat. No. 6,048,861 is 3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid, including the enantiomeric 3(R) and 3(S) forms. Pharmaceutically acceptable salts of this compound are generically encompassed within the scope of U.S. Pat. No. 6,048,861.
However, there is no specific disclosure in the above reference of the newly discovered tris(hydroxymethyl)aminomethyl (xe2x80x9cTRISxe2x80x9d) salt of 3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of structural formula I below.
This invention provides the novel tris(hydroxymethyl)aminomethyl (xe2x80x9cTRISxe2x80x9d) salt of 3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of the following structural formula I: 
or a pharmaceutically acceptable solvate, including hydrate, thereof.
The xe2x80x9cTRISxe2x80x9d salt of the present invention has a chiral center (indicated with an *) at the C-3 position of the nonanoic acid chain and can thus occur as a racemate, racemic mixture, and single enantiomers, with all isomeric forms being included in the present invention. The separate enantiomers, substantially free of the other, are included within the scope of the invention, as well as mixtures of the two enantiomers.
Therefore, one embodiment of the present invention provides the TRIS salt of 3(S)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of structural formula II: 
A second embodiment of the present invention provides the xe2x80x9cTRISxe2x80x9d salt of 3(R)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of structural formula III: 
More specifically, the xe2x80x9cTRISxe2x80x9d salt of the present invention is comprised of one molar equivalent of 3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid anion and one molar equivalent of protonated tris(hydroxymethyl)aminomethane cation.
In a further embodiment of the present invention, the xe2x80x9cTRISxe2x80x9d salts of structural formulae I-III are crystalline.
The crystalline xe2x80x9cTRISxe2x80x9d salt of structural formula I exhibits improved chemical and physical properties over the parent zwitterionic compound of structural formula IV below. This salt therefore has advantages for the preparation of solid pharmaceutical dosage forms containing the pharmacologically active ingredient. Moreover, the xe2x80x9cTRISxe2x80x9d salt has greater solubility in water than the parent zwitterionic compound rendering it more desirable for the preparation of aqueous formulations containing the active ingredient suitable for parenteral, such as intravenous, administration.
The xe2x80x9cTRISxe2x80x9d salt of the present invention, which exhibits potent integrin xcex1vxcex23 antagonist activity, is particularly useful for inhibiting bone resorption, treating and/or preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth.